AZT is the only currently approved agent for the primary therapy of HIV related disease. Resistance to this agent has recently been reported in patients receiving the drug for more than 6 months. However, the clinical significance, the mechanisms and factors relating to the emergence of resistant HIV strains remains unknown. This phenomenon suggests that the development of AZT resistance may, in part, explain subsequent clinical deterioration. In this project we propose to determine the frequency and patterns of emergence of AZT resistant HIV from patients with HIV disease who are on AZT therapy and to evaluate resistance to other antiviral compounds. To accomplish this goal, 100-120 patients will be examined to determine if combination therapy with antivirals administered simultaneously or sequentially affects the emergence of HIV resistant strains, and to determine which combinations maximally inhibit the development of resistance. HIV from patients will be isolated by co-cultivation with normal PBLs, and the sensitivity to AZT and/or other compounds will be evaluated prior to initiation of therapy and at 6 monthly intervals thereafter. The relationship of the development of resistance to the virus burden of the patient (serum P24Ag), and markers of the immune response in peripheral blood (CD4:CD8, serum beta 2-microglobulin, lymphocyte transformation, and interferon-gamma production to specific and non-specific antigens) will also be evaluated. The clinical relevance of the development of HIV drug resistance will be pursued by monitoring and assessing changes in neurobehavioral testing, the frequency of development of opportunistic infections, and changes in weight and other clinical parameters of the study patients. Understanding the natural history of development of resistance should assist in designing changes in the administration of existing therapeutic agents and help identify the novel therapeutic regimens to minimize the emergence of such resistant strains. The development of this information could directly affect patient care practices and outcome.